The HDDC ORGANOID CORE

Welcome to the HDDC Organoid Core Site!

Our Core focuses on intestinal stem cell differentiation. Using the human intestinal organoid model, the Organoid Core uses intestinal stem cells from multiple physiological and disease states, including aging, cystic fibrosis, obesity, and diabetes, to see how physiology and pathology can alter stem cell function.

We are focused on understanding the drivers of intestinal stem cell (ISC) differentiation in the context of human health and disease. To do this, we utilize the organoid culturing system in the setting of a large human intestinal biobank and cutting-edge research technology. We primarily study the hormone-producing enteroendocrine cells (EECs), which have critical roles not only in gastrointestinal (GI) function, but also metabolic regulation, including appetite regulation and insulin production. Our studies derive from four different starting points:

1. Human aging: To understand how EEC differentiation is changed with normal human physiology, we use age (12-19 and 67-80 years of age) to allow us to identify mechanisms driving EEC differentiation in a healthy setting. Using our previously derived differentiation protocols, we found that older adult ISCs (within the organoid system) have more permissive differentiation into EECs compared to pediatric ISCs. We then performed multiomics studies and identified multiple signaling pathways and transcription factors that alter either pediatric or older adult ISCs to regulate EEC differentiation.

2. Human disease: EEC number and hormone production are both altered in multiple disease states, including obesity, type 2 diabetes mellitus, inflammatory bowel disease, and cystic fibrosis. We have found that these changes persist in the organoid state, suggesting that ISCs have cell autonomous changes secondary to these diseases.

3. High throughput screening: We have developed a screening tool to identify activators of EEC differentiation using our organoid model. We have already screened over 600 FDA-approved small molecules and over 1000 plant-derived compounds, leading to the identification of multiple novel compounds and pathways that regulate ISC differentiation.

4. Location within the GI tract: Not all intestinal stem cells are the same throughout the GI system. Using organoids derived from the duodenum, jejunum, ileum, colon, and rectum, we are able to compare transcriptional and epigenetic differences between ISCs as well as EECs derived from different intestinal areas.

These studies are being performed to identify novel mechanisms regulating EEC hormone production in the hopes of developing first-in-class therapeutics for obesity, type 2 diabetes mellitus, and other GI diseases.